Evaluation of CPX-351 Monotherapy in Acute Myeloid Leukemia Secondary to Myeloproliferative Neoplasm

NCT04992949 | Completed Phase 2

• 1 other identifier: CPX-351 TA-SMP
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 34

Brief Summary

The three classic myeloproliferative neoplasms (MPNs) include polycythemia Vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The natural history of these MPNs is the possible progression to acute myeloid leukemia (MPN-blast phase) at variable percentage depending the entity. Leukemic transformation of MPN occurs in 8% to 23% of primary myelofibrosis (PMF) patients in the first 10 years after diagnosis and in 4% to 8% of polycythemia vera (PV) and essential thrombocytosis (ET) patients within 18 years after diagnosis. The risk for leukemic transformation is increased by exposure to cytotoxic chemotherapy. The molecular pathogenesis of MPN-blast phase remains an area of active research. The prognosis of blast phase MPNs is very poor : approximately 50% of the patients are deemed eligible for intensive treatment (ie. conventional induction chemotherapy regimen with anthracyclines and cytarabine). The patients who are not fit for such intensive treatment approach due to age or comorbidities, are treated with Hypomethylating agents, low dose palliative chemotherapy, or supportive care. Nevertheless, there is a need for more effective and better tolerated treatment approaches in order to increase the response rate and hence, the transplant rates which should translate into improved survival. CPX-351 is a new formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar-ratio in liposomes that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy. Based on similarities between post-myelodysplastic syndrome (MDS) and post-MPN secondary AML in terms of disease resistance to chemotherapy, of fragile patient profile, The hypotheses made is that CPX-351 may improve the results of induction chemotherapy without increasing its toxicity and therefore may increase the proportion of patients who could benefit from an allogeneic Stem Cell Transplantation (SCT).

Conditions

Acute Myeloid Leukemia; Myeloproliferative Syndrome

Outcome Measures

Primary Outcomes (2)

• Rate of CR/CRi after first induction therapy

  Rate of CR/CRi according to ELN2017 criteria

  After 28 to 42 days after one cycle of 5 days of CPX351

• Rate of CR/CRi after second induction therapy

  Rate of CR/CRi according to ELN2017 criteria

  If applicable, after 28 to 31 days after a second cycle of 3 days of CPX351

Study Arms (1)

CPX351

EXPERIMENTAL

Induction : patients will receive induction treatment with CPX-351 100 U/m2 on days 1, 3, and 5. Patients who fail to achieve CR/CRi after the induction cycle will be offered a second induction course of CPX-351 100 U/m2 on days 1 and 3, at the investigators' discretion. If CR/CRi is not achieved following the second induction cycle, patients will go off study Consolidation : patients in CR/CRi after induction cycle will receive up to 2 course of CONSOLIDATION therapy with CPX-351 65 U/m2 on days 1 and 3. CPX351 doses could be reduced to 65 U/m2 on day 1 in case of unacceptable toxicity following the previous course.

Drug: CPX-351

Interventions

CPX-351 DRUG

Induction : patients will receive induction treatment with CPX-351 100 U/m2 on days 1, 3, and 5. Patients who fail to achieve CR/CRi after the induction cycle will be offered a second induction course of CPX-351 100 U/m2 on days 1 and 3, at the investigators' discretion. If CR/CRi is not achieved following the second induction cycle, patients will go off study Consolidation : patients in CR/CRi after induction cycle will receive up to 2 course of consolidation therapy with CPX-351 65 U/m2 on days 1 and 3. CPX351 doses could be reduced to 65 U/m2 on day 1 in case of unacceptable toxicity following the previous course. Allo-SCT : patients for whom an allo-SCT is planned will receive a maximum of one consolidation cycle

CPX351

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of newly secondary AML according to WHO 2016 classification following an antecedent of Myeloproliferative Neoplasm including Essential Thrombocythemia (ET), Polycythemia Vera (PV), primary or secondary Myelofibrosis
• Performance status 2 Eastern Cooperative Oncology Group (ECOG) grading.
• Eligible for standard intensive chemotherapy
• Absence of concomitant severe cardiovascular disease which would make intensive chemotherapy impossible, i.e. arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease, reduced left ventricular function assessed by multigated acquisition (MUGA) scan or echocardiogram. Cardiac ejection fraction ≥ 50% by echocardiography ou MUGA
• Patient must have adequate organ function as indicated by the following laboratory values:
• Renal
• Serum creatinine: \< 2 mg/dl OR calculated creatinine clearance\*: ≥ 30 mL/min by MDRD formula for patients with creatinine levels \> 1.5 X institutional Upper Limit Normal (ULN)
• Hepatic
• Serum total bilirubin: ≤ 2.5 X ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels ≥ 2 mg/dL unless Gilbert's Syndrome
• Aspartate-Amino-Transferase (ASAT) and Alanine-Transaminase (ALAT): ≤ 2.5 times ULN
• Alkaline Phosphatase: ≤ 5 X ULN, if \> 2.5 X ULN, then liver fraction should be ≤ 2.5 X ULN \*Creatinine clearance should be calculated per institutional standard
• Life expectancy should be of 12 weeks at least according to investigator evaluation
• Female patients of childbearing potential must have a negative serum pregnancy test (β-hCG) within 72 hours prior to receiving the first dose of CPX-351. Female patients who are not post-menopausal, free from menses for \> 2 years or surgically sterilized, will have to use adequate barrier methods of contraception to prevent pregnancy or agree to abstain from becoming pregnant throughout the study, starting with Visit 1.
• Male patients agree to use an adequate method of contraception for the duration of the study. Men should be advised not to father a child while receiving CPX-351 and for 3 months post study.
• Patients have the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.

You may not qualify if:

• MPN/MDS mixed types
• Prior therapy for AML transformation except for Hydroxyurea
• Uncontrolled undercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance.
• Active and uncontrolled infection
• Current participation or participation in a study with an investigational compound or device within 30 days of initial dosing with study drug
• Patients with acute promyelocytic leukemia.
• Known human immunodeficiency virus (HIV) infection or HIV-related malignancy
• Clinically active hepatitis B or hepatitis C infection.
• Known allergy or hypersensitivity to any component of CPX-351.
• Currently active second malignancy, other than non-melanoma skin cancer and in situ carcinoma of the cervix. Patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for \>3 years or are considered by their physician to be at less than 30% risk of relapse
• Clinical evidence of Central Nervous System Leukemia.
• Pregnancy or breastfeeding during the projected duration of the study.

Sponsors & Collaborators

• French Innovative Leukemia Organisation: lead
• Acute Leukemia French Association: collaborator
• French Intergroup of Myeloproliferative syndromes: collaborator

Study Sites (34)

AMIENS - CHU Amiens Picardie

Amiens, 80054, France

Location

ANGERS - CHU - Maladies du sang

Angers, 49933, France

Location

AVIGNON - Centre Hospitalier

Avignon, 84000, France

Location

BAYONNE - CH de la Côte Basque - Hématologie

Bayonne, 64109, France

Location

AVICENNE - Centre de Recherche Clinique

Bobigny, 93009, France

Location

BREST - Hôpital Morvan

Brest, 29609, France

Location

CAEN - CHU Caen - IHBN

Caen, 14033, France

Location

CLAMART - Hôpital d'Instruction des Armées de Percy

Clamart, 92140, France

Location

Clermont-Ferrand - Chu Estaing

Clermont-Ferrand, 63000, France

Location

CRETEIL - CHU Henri Mondor

Créteil, 94000, France

Location

Grenoble - CHUGA - Hématologie Clinique

Grenoble, 38043, France

Location

LILLE CHU - Hôpital Claude Huriez

Lille, 59037, France

Location

LIMOGES - CHU Dupuytren 1

Limoges, 87042, France

Location

LYON-Centre Léon Bérard

Lyon, 69008, France

Location

MARSEILLE - Institut Paoli-Calmettes

Marseille, 13000, France

Location

MONTPELLIER - Hôpital Saint-Eloi - Hématologie Clinique

Montpellier, 34295, France

Location

NANTES - Hôpital Hôtel Dieu - Hématologie Clinique

Nantes, 44093, France

Location

NICE - Centre Antoine Lacassagne

Nice, 06189, France

Location

NICE - CHU - Hopital Archet 1

Nice, 06202, France

Location

NIMES - CHU Caremeau

Nîmes, 30029, France

Location

ORLEANS - CHR - Hématologie

Orléans, 44100, France

Location

Paris St Antoine

Paris, 75012, France

Location

Paris Saint Louis

Paris, 75475, France

Location

BORDEAUX - Hôpital Haut-Levêque

Pessac, 33600, France

Location

LYON HCL - CH Lyon Sud

Pierre-Bénite, 69036, France

Location

POITIERS - Hôpital La Milétrie - Hématologie Clinique

Poitiers, 86000, France

Location

REIMS - Hôpital Robert Debré - Hématologie Clinique

Reims, 51100, France

Location

RENNES - Hôpital Pontchaillou - Hématologie

Rennes, 35033, France

Location

Strasbourg - Icans

Strasbourg, 67033, France

Location

Toulouse - IUCT Oncopole - Service d'Hématologie

Toulouse, 31059, France

Location

TOURS - Hôpital Bretonneau

Tours, 37000, France

Location

NANCY - CHU de Brabois

Vandœuvre-lès-Nancy, 54500, France

Location

VERSAILLES - Hôpital André Mignot

Versailles, France

Location

Institut Gustave Roussy

Villejuif, France

Location

Related Publications (2)

• Courtier F, Carbuccia N, Garnier S, Guille A, Adelaide J, Cervera N, Gelsi-Boyer V, Mozziconacci MJ, Rey J, Vey N, Chaffanet M, Birnbaum D, Murati A. Genomic analysis of myeloproliferative neoplasms in chronic and acute phases. Haematologica. 2017 Jan;102(1):e11-e14. doi: 10.3324/haematol.2016.152363. Epub 2016 Oct 14. No abstract available.

  PMID: 27742771 BACKGROUND

• Luque Paz D, Jouanneau-Courville R, Riou J, et al. Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation. Blood Adv. 2020;4(19):4887-4897. Blood Adv. 2020 Nov 24;4(22):5651. doi: 10.1182/bloodadvances.2020003711. No abstract available.

  PMID: 33206963 BACKGROUND

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

CPX-351

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Jérôme REY, MD

  French Innovative Leukemia Organisation

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open label multicenter phase II non-randomized study

Study Record Dates

• First Submitted: July 19, 2021
• First Posted: August 5, 2021
• Study Start: March 23, 2022
• Primary Completion: October 15, 2023
• Study Completion: December 4, 2023
• Last Updated: October 29, 2024

Record last verified: 2024-10

Locations

FR (34)